BIOPHYSICAL THEORY AND MODELING |
Adhesive Dynamics Simulation of Neutrophil Arrest with Stochastic Activation
Ellen Krasik 1, Kelly E. Caputo 2 and Daniel A. Hammer 3*
1 UCSF
2 U. Pennsylvania
3 University of Pennsylvania
* To whom correspondence should be addressed. E-mail: hammer{at}seas.upenn.edu.
Submitted on October 3, 2007
Revised on December 14, 2007
Accepted on 22 April 2008
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Abstract |
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The transition from rolling to firm adhesion is a key step in the adhesion cascade that permits a neutrophil to exit the bloodstream and make its way to a site of inflammation. In this paper, we construct an integrated model of neutrophil activation and arrest that combines a biomechanical model of neutrophil adhesion, adhesive dynamics, with fully-stochastic signal transduction modeling, in the form of kinetic Monte Carlo simulation within the microvilli. We employ molecular binding parameters gleaned from literature and from simulation of cell-free rolling mediated by selectin molecules. We create a simplified model of lymphocyte function-associated antigen-1 (LFA-1) activation that links P-selectin glycoprotein ligand-1 (PSGL-1) ligation to integrin activation. The model utilizes an energy profile of various integrin activation states drawn from literature data and permits manipulation of signal diffusivity within the microvillus. Our integrated model recreates neutrophil arrest within physiological time-scales, and we demonstrate that increasing signal diffusivity within a microvillus accelerates arrest. If the energy barrier between free unactivated and free activated LFA-1 increases, the period of rolling before arrest increases. We further demonstrate that, within our model, modification of endothelial ligand surface densities can control arrest. In addition, the relative concentrations of signaling molecules control the fractional activation of the overall signaling pathway and the rolling time to arrest. This paper presents the first fully-stochastic model of neutrophil activation, which, though simplified, can recapitulate significant physiological details of neutrophil arrest yet retains the capacity to incorporate additional information regarding mechanisms of neutrophil signal transduction as they are elucidated.
Key Words:
Adhesive Dynamics, Inflammation, Integrin, Kinetic Monte Carlo, Leukocytes, MAP-kinase
